The annual cost of care for Alzheimer's disease (AD) in the US is currently estimated at $200 billion, and is expected to rise to $1.1 trillion by 2050. Despite these costs and the prevalence of the disease (1 in 8 older Americans has AD), the etiology of AD remains elusive. A major limitation to the study and treatment of AD and other neurodegenerative diseases is the lack of suitable in vivo models. This application aims to solve this problem, using our proprietary RNA TALENs technology to generate knockout and knockin rats to better screen drugs to treat AD and to better model AD progression. In addition to providing products to enhance AD research (the rat models), this application will demonstrate the feasibility of our technology to generate rat models for screening other diseases, especially neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: This project will use our RNA TALENs technology to generate rat stem cells with inactivation/modifications of genes associated with Alzheimer's disease. The results of this project will be a method for rapid generation of knockout and knockin rats for modeling and drug screening, and rats containing specific modification to genes associated with Alzheimer's disease.!